Although coronary reperfusion therapy with chemicals such as thrombolytic agents, or surgery such as coronary artery bypass and percutaneous transluminal coronary angioplasty immediately after ischemic heart diseases such as acute myocardial infarction, arrhythmia, heart failure, etc., increases the survival rate of patients suffering therefrom, the effect thereof remains controversial because of aftereffects including a high recurrence rate of myocardiac infarction or arrhythmia, or cardiac dysfunction or neurocognitive dysfunction [Robert, M. (2003) Ann. Thorac. Surg. 75: S700-708]. Thus, there is a need for a heart protection agent that can delay the progress of ischemic damage to cardiomyocytes and protect reperfusion-induced injuries [Kloner, R. A.; Rezkalla, S. H. (2004) J. Am. Coll. Cardiol. 44: 276-286].
NHE (sodium-hydrogen exchanger) is an ion channel expressed in various cell species, playing an important role in intracellular pH control. Thus far, 7 subtypes have been found, with NHE-1, major subtype in myocardiac cell, known to play a pivotal role in myocardial ischemic-reperfusional injury [Avkiran, M. et al., (2002) J. Am. Coll. Cardiol. 39: 747-753]. NHE-1 doesn't work at a normal physiological pH condition (7.2). NHE-1 is activated by the profound intracellular acidosis (pH=6.4) that accompanies ischemia. The efflux of H+ through the activated NHE-1 is increased, causing intracellular Na+ overload, which leads to intracellular Ca2+ overload through a reverse mode of NCX (Na+/Ca2+ exchanger). An increase of intracellular calcium ions activates enzymes, such as proteases, phospholipase, endonucleases, etc., to cause protein degradation, ROS (reactive oxygen species) increase attributed to lipid metabolism hindrance, DNA damage, and finally, cell injury. This leads to the conclusion that the inhibition of NHE-1 reduces intracellular Na+ ion overload and thus intracellular Ca2+ ion overload, thereby protecting cells from ischemic/reperfusional injury. However, the inhibition of NHE-1 does not induce the intracellular acidosis as the increased intracellular hydrogen ion concentration is controlled by other ion channels.
The pyrazine derivative amiloride, used as a diuretic agent, was found at first to function as an NHE inhibitor [Benos, D J. (1982) A. J. Physiol. 242: C131]. In a rat ischemic heart model, amiloride was observed to improve cardiac function recovery after ischemia/reperfusion by the inhibition of NHE-1. However, amiloride has a problem as a carioprotecting agent due to a lack of selectivity for NHE-1, as it was found to inhibit NHE-2 and sodium channels as well as NHE-1.
Hence, extensive research has been done in order to develop the agents specific for NHE-1, and Hoechst Marion Roussel (now Aventis) succeeded in developing cariporide (HOE-694), a benzoyl guanidine derivative highly specific for NHE-1 [Scholz, W. et. al., (1993) Br. J. Pharmacol. 109: 562]. Almost all of the NHE-1 inhibitors known so far are acylguanidines, as exemplified by the selective NHE-1 inhibitors zoniporide, sabiporide, SM-20220, BMS-284640, etc.
It was found that the protective effects of NHE-1 inhibitors on ischemic reperfused hearts, that is, apoptosis or necrosis reduction, functional recovery of injured myqcardium, arrhythmia reduction, and metabolic status improvement, can be achieved by reducing the intracellular overload of sodium and calcium ions [Karmazyn, M. (2002) Science & Medicine: 18-26]. Hence, functioning as cardioprotectives against ischemia/reperfusion injury, selective NHE-1 inhibitors can be applied to the patients undergoing reperfusion therapy including coronary artery bypass, percutaneous transluminal coronary angioplasty and/or thrombolytics for acute myocardiac infarction, and therefore will live up to the hope of treatment and prevention of a broad spectrum of ischemic heart diseases including heart failure, arrhythmia, etc.
Leading to the present invention, the intensive and thorough research on selective NHE-1 inhibitors, conducted by the present inventors, resulted in the finding that benzothiophen-2-carbonylguanidine derivatives as selective inhibitors of NHE-1, are effective in functional recovery of ischemia/reperfusion-induced myocardial injury, and neuroprotective against apoptosis, in addition to having a significant reduction in infarction size as measured in cerebral and cardiac ischemia models, thereby greatly contributing to the treatment and prevention of ischemic heart and brain diseases.